Molecular characterization of three gonad cell lines
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December 18, ; Accepted date: January 06, ; Published date: Hair Ther Transplant 4: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The Hair Follicle HF is a vital component of mammalian skin and represents a unique, highly regenerative system that undergoes phases of rapid growth, regression, and resting periods. The hair cycling is of profound clinical relevance since majority of the hair growth disorders occur as a result of cycle changes.
The influence of many molecules governing the formation of HF has been investigated and many of important cycle mediators have been identified. Cellular and molecular events during cycling are controlled by bitgood and mcmahon 1995 honda network of sequential activation of autocrine, paracrine and endocrine signaling pathways.
Despite considerable progress in this area, the key elements of cycle control have not been identified. Therefore, for the most common hair disorders several agents are available, even none of these is curative or preventive. The one of the prime challenges of hair research is a better understanding of the molecular controls of hair cycling and developing drug which would effectively manipulate the cycle.
Future therapy strategies will be based on new and better knowledge about the HF biology. Until than, alopecia areata, telogen effluvium and androgenetic alopecia, will remain unsolved medical problems. The Hair Follicle HF is a vital component of mammalian skin. Thick scalp hair gives protection from actinic damage, while specialized nasal hairs, eyebrows and eyelashes have some environmental protective role.
HF is also involved in bitgood and mcmahon 1995 honda perception as a functionally distinct mechanosensory organ, giving the wide tactile sensation range of covered skin surface [ 1 ]. Beside the sensory activity role, hair exerts a function of thermoregulation, physical protection, tissue renewal and regeneration, and serves as an instrument of psychosocial communication [ 2 ].
Production of a hair is the primary and the most bitgood and mcmahon 1995 honda function of HF. Hair growth does not take place continuously, but in a strictly defined cyclic model that includes periodic regeneration of follicles [ 3 ].
A synchronized cycle, seen in mammals, is preparing hair coat for environmental seasonal changes. The purpose of unsynchronized cycle which is seen in human species is not so obvious, but may include cleaning the skin surface of debris and parasitesand secretion of some chemical compounds via bitgood and mcmahon 1995 honda [ 4 ]. Hair growth disorders can be attributed, at large, to a changes in the normal dynamic behaviour of the HF [ 5 ].
Since the cycle is regulated by various hormones and growth factors produced both inside and outside the follicles, even small environmental changes may lead to a shortening of the anagen, catagen phase induction, and increasing the number of telogen bitgood and mcmahon 1995 honda [ 6 ].
Telogen effluvium, Androgenetic Alopecia AGAand Alopecia Areata AAthe frequent hair loss disorders in clinical practice, exemplify how discrete cycling changes translate into significant clinical problems.
Therefore, knowing the hair cycle is necessary for understanding the pathogenesis of hair diseases in general. Current hair treatment strategies are symptomatic and nonspecific so nowadays researches aim at developing new, targeted methods. Future strategies planning specific hair disorders therapy will be based on new and better knowledge about the HF biology.
The hair follicle is perfect and clinically relevant model for biology research. It represents a complex miniorgan that consists of multiple different cell populations which are distinct in their location, function and protein expression characteristics [ 478 ].
The HF is also a uniquely dynamic system that undergoes continuous cycling throughout adult life during which elements of its own morphogenesis are recapitulated [ 9 ]. This miniature organ during the normal human lifespan regenerates itself more than 8 to 10 times [ 210 ]. Regarding the origin of its structures, the mature HF can be divided into the mesenchymal part, consisting of the Dermal Papilla DP with connective tissue sheath, and the epithelial part, including transient amplifying cells of the hair matrix that envelope the DP, hair shaft, inner root sheath and outer root sheath.
Coordination between epithelial and mesenchymal portions of HF as well bitgood and mcmahon 1995 honda bi-directional communication between the pilosebaceous unit and its innervation and vasculature is bitgood and mcmahon 1995 honda to maintain the cyclic hair follicle growth [ 14 - 16 ]. Functionally, HF can be divided into upper permanent part and deep lower part including the hair bulb which is subject of great changes during the cycle. Bulge zone is the lowest part of the permanent HF segment and it is histological evident as unilateral thickening of the outer root sheath [ 17 ].
It is inhabited by epithelial stem cellsprecursors of melanocytes, mast cells and Langerhans cells. Thanks to bulge stem cells, HF regenerates itself [ 1819 ]. SCs are nonspecific and pluripotenthaving the ability to self-renew and differentiate into multiple cell types.
The classical view of SCs depicts them as slowly cycling, relatively undifferentiated cells, with the ability both for self-regeneration and for supplying the rapidly dividing progenitor population [ 9 ]. Until now, melanocytic SCs, mesenchymal SCs, mast cells precursors, immature Langerhans cells and neuronal SCs were recognized [ 21 - 27 ].
The Dermal Papilla DP functions as the hair signaling center, and represents as a pocket of mesenchymal cells that lies at the hair base [ 28 - 30 ].
The number of DP cells and their secretory activity determines the size of the anagen hair bulbthickness, length, and the hair shaft diameter [ 31 - 33 ]. The HF can be considered an essentially autonomous organ as it is able to grow after dissection from its neurovascular supply and transplantation into another part of the integument [ 34 ]. In addition, isolated human HF can be maintained in organ culture, exhibiting emergent properties of great biological relevance: The hair cycle is traditionally divided into the growth phase anagen I-VIregression phase catagen and resting phase telogen [ 2 ].
Hair loss has recently been recognized as a separate active process that is called exogen, while kenogen is a brief interval in bitgood and mcmahon 1995 honda the HF remains empty [ 37 ]. Anagen phase has significantly higher metabolic activity among matrix keratinocytes that produce the hair fiber and inner root sheath.
It is divided into six subphases defined by specific morphological criteria, one of which is called pro-anagen, including phases I to V. The met-anagen phase follows, which leads bitgood and mcmahon 1995 honda hair growth on the epidermis surface [ 38 ]. During the end of the anagen, follicle lies deep, firmly anchored in the subcutaneous tissue, while the bulb changes the position by moving more superficial, below the insertion of the arrector pili muscle.
Anagen phase ends with the involution of HF, apoptosis and terminal differentiation [ 39 - 41 ]. Catagen is the time of involution. It is a short transitional phase of cycle between anagen and telogen, which lasts between two and four weeks.
In this phase follicle undergoes a series of morphological and molecular changes that are associated with apoptosis. The first sign of involution is termination of bulb melanin production. Bitgood and mcmahon 1995 honda melanocytes stop producing melanin and absorb dendrites, and keratinocytes cease proliferation and undergo terminal differentiation [ 5 ].
During catagen, the population of stem cells located lateral to the dermal papilla is spared from apoptosis, allowing the reproliferation in the early anagen [ 33 ].
After regression, the follicle enters the telogen phase, which is expressed by relative rest in terms of activation and proliferation. Telogen phase lasts three to four months. The hair is no longer firmly anchored in the tissue, the link between bitgood and mcmahon 1995 honda part of hair and follicular sac disappears, and the hair falls out. Recent researchers have found that the hair loss is controlled; active process that significantly differs from inaction during telogen [ 42 ]. Even the nature of the process is not yet solved; the morphology of hair root suggests that this process, called exogen, involves proteolytic events among cells in the base of telogen hair [ 43 ].
Kenogen is interval in which the hair follicle remains empty after the telogen hair loss and before the outbreak of a new anagen hair. Number of hairs in kenogen increases parallel with the number of vellus hair and reducing normal hair cycles, which is the main feature of AGA deterioration [ 44 ]. Since the majority of hair growth disorders occur as a result of the hair cycle changes, HF cycling is bitgood and mcmahon 1995 honda profound clinical relevance.
The concept that skin appendage formation at a given location and time is the result of interacting stimulatory and inhibitory signals exist for the long time; these not only consist of secreted molecules and changes in the expression of receptors, but also of changes in tissue biology and underlie prominent epigenetic controls [ 4546 ]. By recent theory, the cycling is caused by rhythmic signal transducers changes in the bulge zone and dermal papilla region, with complex processes that are the consequences of follicular stem cells and dermal papilla cells interactions.
In any case, cellular and molecular events during differentiation of HF are controlled by a complex network of sequential activation of autocrine, paracrine and endocrine signaling pathways.
This implies variations in the expression or activity of numerous cytokines, hormones, neurotransmitters, transcription factors and enzymes in the key compartments of HF. Hair follicle regeneration begins when signals from the mesenchymederived dermal papilla cells reach multipotent epidermal stem cells in the bulge region.
Signal transducer and activator of transcription 3 Stat3 plays critical roles in biological activities and contributes to HF growth. EGF probably triggers multiplication and proliferation of outer root sheath follicle cells that leads to the formation of new hair follicles.
Another EGF role is probably anagen to catagen transition [ 52 ]. Upregulation of Shh activity functions bitgood and mcmahon 1995 honda a biologic switch that induces resting hair follicles to enter anagen with consequent hair growth. Sonic hedgehog is one of the earliest genes found to be expressed in the hair placode.
Continuous labeling of Shh-expressing cells showed that their progeny, with rare exceptions, form all structures in the HF. Shh expression is necessary also for the embryonic development of hair follicles [ 1054 - 58 ]. It is possible that both of these growth factors are bitgood and mcmahon 1995 honda physiological hair cycle regulators. Human scalp HFs are both a source and a target of TRH, which operates as a potent hair-growth stimulator [ 5961 ]. Polyamines are multifunctional polycationic aliphatic amines which except serving as metabolic and nutrients regulators, also have been bitgood and mcmahon 1995 honda as mediators of key cell functions, such as proliferation, migration and differentiation.
Spermidine is a potent stimulator of human hair growth and a previously unknown modulator of human epithelial stem cell biology [ 6263 ]. Finally, an important role in the regenerating hair follicleplay hair follicle stem cell marker nestin, located in the dermal papilla [ 64 ]. Dickkopf 1 DKK-1 is involved in anagen-to-catagen transition in the hair cycle by regulating the activity of follicular keratinocytes.
Besides, the molecular interaction between downregulating effectors of TNF-asignalling bitgood and mcmahon 1995 honda keratin 17 K17 may be partly responsible for controlling catagen entry by regulating the rate of apoptosis [ 2 ]. Last decade has revealed a pivotal role for the TNF family ligand Ectodysplasin Eda in multiple steps of hair morphogenesis, from initiation to differentiation. Other members of the TNF superfamily such as Rank ligand, lymphotoxins and TNF have recently been linked with sp ecific aspects of skin appendage biology including hair shaft formation, and hair follicle cycling [ 49 ].
Bitgood and mcmahon 1995 honda involved controlling anagen-catagen transformation molecules are neurotrophins NT-3, NT-4, as well as prolactin and retinoids. Prolactin participates in the regulation of anagen and telogen initiation, and is produced by the follicle itself. Recent studies identifie PRL as a major, clinically relevant, novel neuroendocrine regulator of both human keratin expression and human epithelial stem cell biology in situ [ 10506768 ].
The signaling that controls hair cycle resting phase is only partly understood. Telogen concurs with major gene activity changes and some proteins, like estrogen receptor, are noticeably increased, so this phase is not really quiescent as traditionally described.
Bitgood and mcmahon 1995 honda the contrary telogen probably represents a key stage in hair cycle control. BMPs are diffusible molecules involved in a variety of cellular interactions during development. It is proposed that about the stage of terminal division, the balance between BMP and BMP-inhibitory signals regulates survival and specification of hair-cell precursors [ 69 ].
Signaling FGF18 is expressed in a hair stem cell niche throughout telogen, and that it regulates the hair cycle through the non-growth phases. FGF affects follicular morphogenesis, participates in the bitgood and mcmahon 1995 honda of mitotic activity and differentiation. Receptors for this growth factor have been identified in the follicular papilla and in the basal layer of epidermal keratinocytes [ 70 ].
The cycle stage, called exogen, has its own control mechanisms and it is presumed that its regulators are protease cathepsin L and Msx-2 [ 2 ]. Bitgood and mcmahon 1995 honda hormonal influence, autocrine and paracrine factors produced by balding DP cells following Dihydrotestosterone DHT - driven alterations are believed to be key factors involved in male pattern baldness.